The use of illicit and licit drugs continues to be a major public health concern. Many prevention and drug education programs address this issue by attempting to enhance self-esteem. The idea is that increased levels of self-esteem will serve as a protective factor in decreasing the motivation and increasing the resistance to use drugs. This study explored the relationship between area specific self-esteem and adolescent substance use. Participants (n = 700) completed a self-report questionnaire which included items measuring the use and expected use of selected substances. Results indicated significant differences in home and school self-esteem scores between users/expected users and non-users of a given substance for all 14 behavioral measures. Additionally, the peer, home, and school sub-scales as a set were found to distinguish between users and non-users for all 14 behavioral measures. Results should be of value to those designing prevention programming.